US4328153A - Dopaminergic benzazepines - Google Patents

Dopaminergic benzazepines Download PDF

Info

Publication number
US4328153A
US4328153A US06/169,696 US16969680A US4328153A US 4328153 A US4328153 A US 4328153A US 16969680 A US16969680 A US 16969680A US 4328153 A US4328153 A US 4328153A
Authority
US
United States
Prior art keywords
tetrahydro
benzazepine
compound
hydroxyphenyl
dihydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/169,696
Other languages
English (en)
Inventor
L. Martin Brenner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Corp filed Critical SmithKline Corp
Priority to US06/169,696 priority Critical patent/US4328153A/en
Priority to DK288981A priority patent/DK288981A/da
Priority to JP56110622A priority patent/JPS5750966A/ja
Priority to GR65519A priority patent/GR75301B/el
Priority to EP81303263A priority patent/EP0044709B1/en
Priority to DE8181303263T priority patent/DE3162658D1/de
Priority to IE1608/81A priority patent/IE51412B1/en
Priority to AT81303263T priority patent/ATE6642T1/de
Application granted granted Critical
Publication of US4328153A publication Critical patent/US4328153A/en
Assigned to SMITHKLINE BECKMAN CORPORATION reassignment SMITHKLINE BECKMAN CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). EFFECTIVE DATE: 03/04/82 Assignors: SMITHKLINE CORPORATION
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention comprises a group of new chemical compounds which are 3-cycloalkylmethyl-7,8-dihydroxy-6-halo-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepines. These compounds increase blood flow in the kidney by decreasing vascular resistance mainly by means of a dopaminergic effect on peripheral dopamine receptors. As such they are useful for treating hypertension.
  • the compounds of this invention have structures characterized by a 2,3,4,5-tetrahydro-1H-3-benzazepine nucleus substituted by a cycloalkylmethyl group at position 3, a halo at position 6, two hydroxy groups at positions 7 and 8 and a hydroxyphenyl moiety at position 4.
  • the compounds therefore may be represented by the following structural formula: ##STR1## in which R is halo, that is, chloro, bromo, fluoro or iodo and n is an integer of from 1-4. Of particular interest are those compounds of Structure I in which n is 1.
  • the three phenolic hydroxy groups may also be derivatized by forming tri-lower alkanoyl esters.
  • Each of the lower alkanoyl groups has from 2-7 carbon atoms. For convenience in preparation, the same alkanoyl group is used at each position.
  • the pharmaceutically acceptable acid addition salts having the utility of the free bases of Formula I are formed with both inorganic and organic acids, for example: fumaric, ascorbic, succinic, methane sulfonic, ethanedisulfonic, acetic, tartaric, salicylic, citric, gluconic, itaconic, glycolic, benzene sulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • the hydrohalic and especially methane sulfonic acid salts are of particular utility.
  • the compounds of this invention are prepared by a synthetic sequence-the first step of which involves the N-acylation of a known 6-halo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (U.S. Pat. No. 4,160,765) with a cycloalkyl carboxylic acid or its acid halide to give the N-cycloalkylcarbonyl compound which is then reduced with metallic reducing agent such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, lithium triethylborohydride, sodium trimethoxyborohydrate and other metallic hydride reducing agents.
  • metallic reducing agent such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, lithium triethylborohydride, sodium trimethoxyborohydrate and other metallic hydride reducing agents.
  • the reducing step is conveniently carried out in a solvent in which the reactants are soluble such as tetrahydrofuran at temperatures from 40° up to reflux temperature.
  • the desired products are isolated by methods known to the art.
  • acylation-reduction steps can be combined using a cycloalkylcarboxylic acid and the secondary base as starting material with sodium borohydride in tetrahydrofuran at 50°-60° until the reaction is complete.
  • Alternative ether cleaving agents are pyridine hydrochloride, 48% aqueous hydrogen bromide, aluminum chloride or bromide in a suitable organic solvent such as benzene or carbon disulfide, 57% hydrogen iodide, hydrogen fluoride-antimony pentafluoride or trifluoromethylsulfonic acid in thioanisole.
  • a suitable organic solvent such as benzene or carbon disulfide
  • hydrogen iodide hydrogen fluoride-antimony pentafluoride or trifluoromethylsulfonic acid in thioanisole.
  • the product is isolated by methods known to the art.
  • the renal dopaminergic activity of the compounds of this invention was demonstrated by monitoring mean arterial blood pressure (MAP), mean renal blood flow (RBF), renal vascular resistance (RVR) and heart rate (HR) in a normal anesthetized dog in a standard pharmacological procedure.
  • MAP mean arterial blood pressure
  • RVF mean renal blood flow
  • RV renal vascular resistance
  • HR heart rate
  • the selected compound is administered by intravenous infusion and is expressed as ⁇ g/kg/min. Each dose is infused for five minutes.
  • a clinically useful compound, dopamine was run as a positive control.
  • the desired vasodilator activity accompanied by increase in renal blood flow was observed at doses of 30 and 300 ⁇ g/kg/min.
  • the pharmacodynamic methods of this invention comprise administration of an active nontoxic quantity of a compound of Formula I, one of its pharmaceutically acceptable acid addition salts or one of its O-lower alkanoyl esters internally, preferably either orally or parenterally, to a human or animal patient in need or renal vasodilation.
  • the primary desired effect on the kidney is to decrease vascular resistance and increase blood flow.
  • the effect is similar to the renal effects of dopamine and like clinical effects may be thereby realized such as in treating hypertension or other abnormal cardiovascular conditions.
  • the route of administration may be any that effectively transports the active ingredient to the renal receptors but oral, rectal, intravenous or subcutaneous routes of administration are conveniently used.
  • the compound of Formula I is administered in a nontoxic quantity sufficient to induce renal vasodilatation.
  • the active ingredient is combined with a pharmaceutical carrier and administered to the patient from 1-5 times daily as necessary to effect the desired pharmacodynamic result.
  • the daily dosage is based on total quantities of the base of from about 200 mg to about 1 g per day, administered preferably as 100-500 mg of base per dosage unit which is administered from 1-5 times daily orally.
  • the parenteral dosage regimen would be lower than the oral regimen.
  • the daily dosage regimen is selected with the conditions known to be factors in the art, for example, the age and weight of the subject, the severity of the clinical disorder, the route of administration and the relative potency of the active ingredient compared to the activity of dopamine in the test systems described hereafter.
  • compositions of this invention having renal dilating activity which are of use for treating hypotensive patients are prepared in conventional dosage unit forms by incorporating a compound of Formula I, or a pharmaceutically acceptable acid addition salt or ester derivative thereof, with a nontoxic pharmaceutical carrier according to accepted procedures in a nontoxic amount sufficient to produce the desired pharmacodynamic activity in a subject, animal or human.
  • the compositions will contain the active ingredient in an active but nontoxic amount selected from about 100 mg to about 500 mg preferably about 125-350 mg of active ingredient calculated as the base per dosage unit.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.
  • liquid carriers are isotonic saline for parenteral use or syrup, peanut oil, olive oil, water and the like for soft gelatin capsules.
  • the carrier or diluent may include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • Such sustained release products as well as derivatives which may be gradually metabolized to the active parent can be employed to prolong the biological activity of the compounds of this invention.
  • a wide variety of pharmaceutical forms can be employed ranging from rectal suppositories to sterile solutions for parenteral or injectable use.
  • a solid carrier for oral administration the preparation can be tableted, placed in a hard gelatin capsule in powder, regular or sustained release pellet or tablet form, or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g.
  • a liquid carrier the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to give the desired end product.
  • the yellow oil in chloroform was passed over a silica gel column and eluted using 2% methanol-chloroform to give 2.1 g of the desired base.
  • the base was converted with hydrogen chloride-methanol to 1.58 g (69%) of the hydrochloride salt of 3-cyclopropylmethyl-6-chloro-7,8-dimethoxy-1-(p-methoxy-phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 146°-149°.
  • trimethoxyhydrochloride (0.98 g, 0.0022 m) in 25 ml of methylene chloride was cooled to -15° then reacted with a mixture of 1.2 ml (0.013 m) of boron tribromide and 10 ml of methylene chloride. After stirring at -15° for one half hour and at room temperature for 2 hours, the mixture was cooled and quenched several times with methanol, the last time with a few drops of 48% hydrogen bromide.
  • This compound (150 mg) is mixed with 150 mg of lactose and 2 mg of magnesium stearate then filled into hard gelatin capsule which is administered orally to a hypertensive patient 5 times daily.
  • Example 2 The procedure of Example 2 is repeated with 6-iodo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine and cyclopentanecarboxylic acid chloride as starting materials to give the N-cyclopentylcarbonyl compound then 3-cyclopentylmethyl-6-iodo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, and finally 3-cyclopentylmethyl-6-iodo-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
  • 6-Bromo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3 g) is reacted with cyclohexylcarboxylic acid in the presence of sodium borohydride as in Example 1 to give 6-bromo-3-cyclohexylmethyl-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine base and, after treatment with boron tribromide, 6-bromo-3-cyclohexylmethyl-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
US06/169,696 1980-07-17 1980-07-17 Dopaminergic benzazepines Expired - Lifetime US4328153A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US06/169,696 US4328153A (en) 1980-07-17 1980-07-17 Dopaminergic benzazepines
DK288981A DK288981A (da) 1980-07-17 1981-06-30 Fremgangsmaade til fremstilling af dopaminergiske benzazepiner
JP56110622A JPS5750966A (en) 1980-07-17 1981-07-14 Novel dopamine benzazepine, manufacture and medicinal composition containing same
GR65519A GR75301B (enrdf_load_stackoverflow) 1980-07-17 1981-07-15
EP81303263A EP0044709B1 (en) 1980-07-17 1981-07-16 New dopaminergic benzazepines
DE8181303263T DE3162658D1 (de) 1980-07-17 1981-07-16 New dopaminergic benzazepines
IE1608/81A IE51412B1 (en) 1980-07-17 1981-07-16 New dopaminergic benzazepines
AT81303263T ATE6642T1 (de) 1980-07-17 1981-07-16 Dopaminerg wirkende benzazepine.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US06/169,696 US4328153A (en) 1980-07-17 1980-07-17 Dopaminergic benzazepines

Publications (1)

Publication Number Publication Date
US4328153A true US4328153A (en) 1982-05-04

Family

ID=22616789

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/169,696 Expired - Lifetime US4328153A (en) 1980-07-17 1980-07-17 Dopaminergic benzazepines

Country Status (8)

Country Link
US (1) US4328153A (enrdf_load_stackoverflow)
EP (1) EP0044709B1 (enrdf_load_stackoverflow)
JP (1) JPS5750966A (enrdf_load_stackoverflow)
AT (1) ATE6642T1 (enrdf_load_stackoverflow)
DE (1) DE3162658D1 (enrdf_load_stackoverflow)
DK (1) DK288981A (enrdf_load_stackoverflow)
GR (1) GR75301B (enrdf_load_stackoverflow)
IE (1) IE51412B1 (enrdf_load_stackoverflow)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ203064A (en) * 1982-02-24 1985-05-31 Smithkline Beckman Corp R-or s-6-chloro-7,8-dihydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1h-3-benzazepine
JP2972704B2 (ja) 1998-03-31 1999-11-08 静岡日本電気株式会社 電子機器のバッテリ収納構造

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3609138A (en) * 1967-12-22 1971-09-28 Ciba Geigy Corp 1-aryl-3-benzazepines
CH555831A (de) * 1967-02-17 1974-11-15 Scherico Ltd Verfahren zur herstellung von neuen benzazepinen.
US4011319A (en) * 1975-07-02 1977-03-08 Smithkline Corporation Pharmaceutical compositions and methods involving benzazepine derivatives
US4197297A (en) * 1976-11-17 1980-04-08 Smithkline Corporation 6-Halo-7,8-dihydroxy-1-(hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepines

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2520264A (en) * 1947-08-26 1950-08-29 Maltbie Lab Inc Substituted 3, 1-benz-2, 3, 4, 5-tetrahydroazepines
CA974989A (en) * 1968-03-11 1975-09-23 Wallace And Tiernan Inc. Process for preparing 1,2,4,5-tetrahydro-3h,3-benzazepines and products obtained thereby
US4160765A (en) * 1976-11-17 1979-07-10 Smithkline Corporation Method for 6-bromination of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds
US4165372A (en) * 1977-11-17 1979-08-21 Smithkline Corporation 6-Carboxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds and use as dopaminergic agents
US4171359A (en) * 1978-04-12 1979-10-16 Smithkline Corporation Benz-tetrasubstituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines
US4251525A (en) * 1979-05-25 1981-02-17 Smithkline Corporation 3-Allyl-7,8-dihydroxy-6-halo-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH555831A (de) * 1967-02-17 1974-11-15 Scherico Ltd Verfahren zur herstellung von neuen benzazepinen.
US3609138A (en) * 1967-12-22 1971-09-28 Ciba Geigy Corp 1-aryl-3-benzazepines
US4011319A (en) * 1975-07-02 1977-03-08 Smithkline Corporation Pharmaceutical compositions and methods involving benzazepine derivatives
US4197297A (en) * 1976-11-17 1980-04-08 Smithkline Corporation 6-Halo-7,8-dihydroxy-1-(hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepines

Also Published As

Publication number Publication date
JPS5750966A (en) 1982-03-25
EP0044709B1 (en) 1984-03-14
DE3162658D1 (de) 1984-04-19
EP0044709A1 (en) 1982-01-27
IE811608L (en) 1982-01-17
DK288981A (da) 1982-01-18
ATE6642T1 (de) 1984-03-15
IE51412B1 (en) 1986-12-24
GR75301B (enrdf_load_stackoverflow) 1984-07-13

Similar Documents

Publication Publication Date Title
US4582847A (en) 4-chloro-2-phenylimidazole-5-acetic acid derivatives and use as diuretics and hypotensives
US4359464A (en) 3-Furylmethyl-6-halo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines and antihypertensive use thereof
AU629585B2 (en) Heterocyclic compounds
EP0040956B1 (en) 8-substituted 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines
US3405134A (en) Quinuclidyl esters of aromatic acids
US4314944A (en) 4-Aminoalkyl-7-hydroxy-2(3H)-indolones
US4251525A (en) 3-Allyl-7,8-dihydroxy-6-halo-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives
US4563465A (en) Treatment of migraine with substituted tropyl benzoate derivatives
US4328153A (en) Dopaminergic benzazepines
EP0380355B1 (en) Carbamates of 6-chloro-7,8-dihydroxy-1-(4'-Hydroxyphenyl)-2,3,4,5-tetra-hydro-1H-3-benzazepine as prodrugs
US4218454A (en) N-αMethylcyclopropylmethyl derivatives of normorphine and noroodeine, and analgesic compositions and methods employing the normorphine derivatives
US4340601A (en) Dopaminergic isoquinolines
US4585866A (en) Treatment of migraine with substituted tropyl benzoate derivatives
EP0106486A2 (en) Improvements in or relating to novel octahydrobenz(f)isoquinolines
SU1053749A3 (ru) Способ получени 1,2-бис-(никотинамидо)-пропана или его солей с фармацевтически приемлемой кислотой
US4269843A (en) N-Sec-alkyl analogs of norcodeine and normorphine and analgesic compositions and methods employing the normorphine derivatives
US4707484A (en) Substituted piperidinomethylindolone and cyclopent(b)indolone derivatives
US4282227A (en) Renal vasodilating 3,4-dihydroxyphenyltetrahydrothienopyridines
US4254140A (en) 4-(2-Aminoethyl)-7-hydroxy-2-methyl-2,3-dihydrobenzofurans
US4285938A (en) 7,8-Dihydroxy-1-(sulfamylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives
US4751232A (en) Pyrrolizidine derivative and pharmaceutical composition thereof
US4255445A (en) 8-Hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines
JPS6040423B2 (ja) ユーフエニル―２，３，４，５―テトラヒドロ―１ｈ―３―ベンズアゼピン類
JP3639326B2 (ja) 新規なアコニチン型化合物及び鎮痛・抗炎症剤
KR800000537B1 (ko) 아미노-페닐-에탄올아민의 제조방법

Legal Events

Date Code Title Description
AS Assignment

Owner name: SMITHKLINE BECKMAN CORPORATION

Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769

Effective date: 19820304

Owner name: SMITHKLINE BECKMAN CORPORATION, PENNSYLVANIA

Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769

Effective date: 19820304

STCF Information on status: patent grant

Free format text: PATENTED CASE